Revolution in a capsid with RNA packaging
Artificial nucleocapsid proteins, which could be analogous to those used by viruses to package their genomes, are a promising way to protect and deliver RNAs. Using an escalating challenge from nucleases, Tetter et al. developed a protein that forms multimeric, spherical cages into a highly efficient capsid that selectively packages its own coding RNA. Cryo-electron microscopy of the final design and intermediates revealed a stepwise expansion in size made possible by destabilization of amino acid substitutions and a domain swap resulting in a change in oligomerization interfaces for the base units of the cage. In addition to altering the protein, controlled development resulted in changes in the coding RNA structure that allowed efficient uptake relative to other cellular RNAs.
Science, abg2822, this issue p. 1
Viruses are ubiquitous pathogens with global impact. Encouraged by the hypothesis that their earliest ancestors recruited host proteins for virion formation, we have used rigorous laboratory development to convert a bacterial enzyme lacking affinity for nucleic acids into an artificial nucleocapsid that efficiently packs and protects multiple copies of its own coding messenger RNA. Revealing remarkable convergence on the molecular characteristics of natural viruses, the accompanying changes rearranged the protein building blocks into an intertwined 240 subunit icosahedric capsid impermeable to nucleases, and the emergence of a robust RNA strain-loop packaging cassette specificity. In addition to presenting a plausible evolutionary pathway for viral viruses, these findings highlight practical strategies for developing non-viral carriers for various vaccine and delivery applications.